Mechanobiology describes the relationship between a cell and its environment; how a cell can detect, measure and respond to the rigidity of its substrate and how these processes apply to larger biological systems.

The cytoskeleton is a highly dynamic network of filamentous proteins that enables the active transport of cellular cargo, transduces force, and when assembled into higher-order structures, forms the basis for motile cellular structures that promote cell movement. Learn More

Cell membranes are highly enriched in signaling receptors, transmembrane mechanosensors, pumps and channels, and, depending on their makeup, can recruit and retain a pool of mechanosensors important in the field of mechanobiology. Learn More

The detection of mechanical signals, and their integration into biochemical pathways, is integral to the cell’s ability to sense, measure and respond to its physical surroundings. Mechanosignl and enable communication between neighbouring cells. Learn More

Genome regulation encompasses all facets of gene expression, from the biochemical modifications of DNA, to the physical arrangement of chromosomes and the activity of the transcription machinery. Learn More

Development in higher order organisms commences at conception and continues into old age. In the earliest stages of development, the physical properties of the microenvironment can direct cell differentiation, and initiate the coordinated movement of groups of cells to establish the patterns that will define how the body is arranged. Learn More

Insights into disease etiology and progression, the two major aspects of pathogenesis, are paramount in the prevention, management and treatment of various diseases. While many people will be genetically predisposed to a given disease, the mechanical properties of the tissue or cellular environment can also contribute to disease progression or its onset.Learn More

What are nucleosomes?

In order to fit DNA into the nucleus, it must be packaged into a highly compacted structure known as chromatin. In the first step of this process DNA is condensed into an 11 nm fiber that represents an approximate 6-fold level of compaction [1]. This is achieved through nucleosome assembly.

Each nucleosome consists of histone octamer core, assembled from the histones H2A, H2B, H3 and H4 (or other histone variants in some cases) and a segment of DNA that wraps around the histone core. Adjacent nucleosomes are connected via “linker DNA”.

The nucleosome is the smallest structural component of chromatin, and is produced through interactions between DNA and histone proteins. Here, a histone octamer is formed from the histones H2A, H2B, H3 and H4, although in some cases other histone variants may also be found in the core (e.g., H2A.Z, MacroH2A, H2a.Bbd, H2A.lap1, H2A.X, H3.3, CenH3 and others [1]). A 147bp segment of DNA then wraps around the histone octamer 1.75 times, thus completing the formation of a single nucleosome.

Of course, a single nucleosome will not form in isolation but is instead part of a wider process, whereby multiple nucleosomes form in a linear fashion along the DNA molecule. This ultimately produces the 11 nm fiber, which is traditionally described, based on its appearance, as “beads on a string” [2]. Here, adjacent nucleosomes are connected via “linker DNA”, which is usually bound to the H1 histone and is between 20-80 bps long. Additionally, flexible histone tails which originate from the histone octamer extend away from nucleosomal DNA and can interact with other nucleosomes, stabilizing more complex 3D structures [3]. In other words, specific nucleosomes can be far apart with respect to their linear sequence, but within interacting distance in the context of higher order chromatin structure [1].

Alternative nucleosome conformations (reviewed in [1]) may arise due to spontaneous unwrapping and rewrapping of DNA around the histone core, as well as due to variations in histones themselves. Moreover, nucleosomes are highly dynamic and can undergo spontaneous sliding, “splitting” or even complete dissociation.

The level of compaction attained through the formation of the 11 nm nucleosome fiber is insufficient to package the whole genome into the nucleus. Instead, this fiber forms the basis for other higher order chromatin structures that are established through additional folding and bending events.

Intermediate chromatin structures

Despite the extensive knowledge already gained on the structure of the 11 nm nucleosome fiber, as well as metaphase chromosomes, the intermediate chromatin structures commonly described are largely hypothetical and yet to be observed in vivo.

30 nm chromatin fibers are considered to exist in the form of so called solenoid or zigzag. The main feature of solenoid model is that nucleosomes follow each other along the same helical path, and interactions between the histone cores occur sequentially (1, 2, 3 and so on). Therefore, solenoid is also referred to as “one start model”. In zigzag, on the other hand, linker DNA connects two opposing nucleosomes, creating a structure where the alternate histone cores become interacting partners (i.e., 1 and 3, 2 and 4 and so on). Therefore, zigzag is considered as a “two start model”, which is indicated in the figure (B) by two different colors of histone cores: yellow interacting nucleosome partners (1, 3, etc.) as opposed to the violet nucleosome row (2, 4, etc.).

Two popular models that were proposed based on in vitro data are the solenoid and zigzag. In each case, the 11 nm nucleosome fiber undergoes additional folding to form a 30 nm fiber [4][5] with the manner of folding for a particular region depending on the internucleosomal linker length and the presence of linker histone H17 [6]. In the one-start solenoid model, bent linker DNA sequentially connects each nucleosome cores, creating a structure where nucleosomes follow each other along the same helical path [4][7]. Alternatively, in the two-start zigzag model, straight linker DNA connects two opposing nucleosome cores, creating the opposing rows of nucleosomes that form so called “two-start” helix. In zigzag model, alternate nucleosomes (for example, N1 and N3) become interacting partners [5][8]. Interestingly, some studiesoffer a model, where intermediate 30 nm fibers contain both the solenoid and zigzag conformations [9], suggesting instead that observations made in in vitro experiments might be an isolation artifact due to strictly cationic low-salt environment or chemical cross-linking (e.g., glutaraldehyde fixation). Consequently, new models of 11 nm fiber compaction have been proposed (e.g., chromonema, chromatin hub, hybrid chromonema/chromatin hub, fractal [10][11][12]), but no common conclusion has been reached yet.

One aspect shared by most of the models for higher order chromatin organization is the dynamic existence of decondensed loops among more compact chromatin structures. In most cases, higher order chromatin has to be decondensed to a nucleosome structural level in order to transcribe genes [13][14]. The length of the decondensed chromatin loop can sometimes exceed the area occupied by the chromosome territory, to which the loop belongs, allowing it to intermingle into the neighbouring chromosome territory [15].

More Questions FAQ

A series of processes must take place that enable the cell to package DNA within the confines of the nucleus whilst retaining its ability to transcribe and duplicate the entire DNA sequence and maintain its integrity. This is achieved through an elaborate process of DNA condensation that sees DNA packaged into 46 chromosomes (or 23 chromosome pairs) in humans. Read more..

The final step in translation is ribosome recycling, which sees the ribosome split into its smaller subunit parts and prepare for another round of translation. In eukaryotes this means the 80S ribosome splits into its 40S and 60S subunits. Read more..

What happens during the elongation stage of translation?Sruthi Jagannathan2017-12-19T16:46:46+08:30

Elongation occurs over several well-defined steps, beginning with the recognition of the mRNA codons by their corresponding aminoacyl-tRNA. Association with the mRNA occurs via the ribosomal A site and is influenced by various elongation factors. Read more..

The first step in translation is known as initiation. Here, the large (60S) and small (40S) ribosomal units are assembled into a fully functional 80S ribosome. This is positioned at the start codon (AUG) of the mRNA strand to be translated. Read more..

Traditionally, chromatin is classified as either euchromatin or heterochromatin, depending on its level of compaction. Euchromatin has a less compact structure, and is often described as a 11 nm fiber that has the appearance of ‘beads on a string’ where the beads represent nucleosomes and the string represents DNA. In contrast, heterochromatin is more compact, and is often reported as being composed of a nucleosome array condensed into a 30 nm fiber. Read more..

Despite 20,000 genes being present in each haploid nucleus, the number of transcription foci is limited to around 2000. These transcription foci, also known as transcriptional factories are distinct submicron nuclear regions that are associated with nascent RNA production and are enriched in RNA polymerase II (RNA pol II) complexes. Read more..

With the development of high-throughput biochemical techniques, such as 3C (‘chromosome conformation capture’) and 4C (‘chromosome conformation capture-on-chip’ and ‘circular chromosome conformation capture’), numerous spatial interactions between neighbouring chromatin territories have been described. Together, these observations and physical simulations have led to the proposal of various models that aim to define the structural organization of chromosome territories. Read more..

As an integral part of cellular behavior, cells are sensitive to matrix rigidity, local geometry and stress or strain applied by external factors. In recent years, it has been established that an extensive network of protein assembly couples the cytoskeleton to the nucleus and that condensation forces of the chromatin balance cytoskeletal forces resulting in a prestressed nuclear organization. Read more..

Cells must replicate their DNA before they can divide. This ensures that each daughter cell gets a copy of the genome, and therefore, successful inheritance of genetic traits. DNA replication is an essential process and the basic mechanism is conserved in all organisms. Read more..

While chromosome territory dynamics is believed to regulate gene expression through the redistribution of genes and the subsequent co-localization of these genes with transcription machinery, changes are also commonly made to the chromosome structure at a ‘local’ level. Although these changes do not necessarily involve the redistribution of genes, they do have a significant influence on gene regulation. Read more..

The spatial organization of chromatin within the 3-dimensional space of a chromosome territory enables the co-localization of co-transcribed genes and their transcriptional foci. Many gene positioning studies have shown that individual genes often loop out of their chromosomal territory to co-localize with transcription factories. Read more..

What is the chromatin polymer model of chromosome territory organization?steve2018-01-19T15:08:09+08:30

The chromatin polymer models assume a broad range of chromatin loop sizes and predict the observed distances between genomic loci and chromosome territories, as well as the probabilities of contacts being formed between given loci. These models apply physics-based approaches that highlight the importance of entropy for understanding nuclear organization… Read more…

What is the Fraser and Bickmore model of chromosome territory organization?steve2018-01-19T15:06:27+08:30

The Fraser and Bickmore model emphasizes the functional importance of giant chromatin loops, which originate from chromosome territories and expand across the nuclear space in order to share transcription factories. In this case, both cis- and trans- loops of decondensed chromatin can be co-expressed and co-regulated by the same transcription factory… Read more…

What is the interchromatin network (ICN) model of chromosome territory organization?steve2018-01-19T15:12:33+08:30

The interchromatin network (ICN) model of chromosome territory organization predicts that intermingling chromatin fibers/loops can make both cis- (within the same chromosome) and trans- (between different chromosomes) contacts. This intermingling is uniform and makes distinction between the chromosome territory and interchromatin compartment functionally meaningless… Read more…

With the development of high-throughput biochemical techniques, such as 3C (‘chromosome conformation capture’) and 4C (‘chromosome conformation capture-on-chip’ and ‘circular chromosome conformation capture’), numerous spatial interactions between neighbouring chromatin territories have been described. These descriptions have been supplemented with the construction of spatial proximity maps for the entire genome (e.g., for a human lymphoblastoid cell line). Together, these observations and physical simulations have led to the proposal of various models that aim to define the structural organization of chromosome territories… Read more…

During interphase, each chromosome occupies a spatially limited, roughly elliptical domain which is known as a chromosome territory (CT). Each chromosome territory is comprised of higher order chromatin units of ~1 Mb each. These units are likely built up from smaller loop domains. Read more..

In order to fit DNA into the nucleus, it must be packaged into a highly compacted structure known as chromatin. In the first step of this process DNA is condensed into a 11 nm fiber that represents an approximate 6-fold level of compaction. This is achieved through nucleosome assembly. Read more..

A series of processes must take place that enable the cell to package DNA within the confines of the nucleus whilst retaining its ability to transcribe and duplicate the entire DNA sequence and maintain its integrity. This is achieved through an elaborate process of DNA condensation that sees DNA packaged into 46 chromosomes (or 23 chromosome pairs) in humans. Read more..

The human genome contains over 3 billion base pairs or nucleotides. These nucleotides, which are arranged in a linear sequence along DNA (deoxyribonucleic acid), encode every protein and genetic trait in the human body… Read more…

How does the cytoskeleton influence nuclear morphology and positioning?steve2018-01-19T16:12:40+08:30

Work by Mazumder et al. ascertained the active involvement of cytoskeletal forces in determining nuclear morphology. Change in nuclear size upon perturbation of actomyosin and microtubules affirmed their roles in exerting tensile and compressive forces respectively on the nucleus, correlating with their functions in the cellular context , … Read more…

How does the cytoskeleton couple the plasma membrane to the nucleus?steve2018-01-19T16:24:16+08:30

Cytoskeletal filaments bridge the nucleus to the plasma membrane, which in turn is anchored at sub-cellular sites to extracellular substrates via a plethora of proteins that form focal adhesions (FAs). FAs are points of cross-talk between transmembrane integrin receptors and the cytoplasmic filaments and thus are key sites for both biochemical and mechanotransduction pathways… Read more…

How is the organization and function of the genome regulated?steve2017-12-18T14:43:41+08:30

Genome regulation encompasses all facets of gene expression, from the biochemical modifications of DNA, to the physical arrangement of chromosomes and the activity of the transcription machinery.The genome regulation programs that cells engage control which proteins are produced, and to what level. The programs are established during stem cell differentiation, and therefore dictate the specialized functions that the cell will carry out throughout its lifetime… Read more…

What are intermediate chromatin structures?Andrew Wong2017-12-19T15:02:43+08:30

Despite the extensive knowledge already gained on the structure of the 11 nm nucleosome fiber, as well as metaphase chromosomes, the intermediate chromatin structures commonly described are largely hypothetical and yet to be observed in vivo.Two popular models that were proposed based on in vitro data are the solenoid and zigzag. Read more..